187-2017

REFERENCES

Pathophysiology of Airway Disease

Fahy JV: Type 2 inflammation in asthma: Present in most, absent in many. Nat Rev Immunol 2015;15:57.

Kim HY, DeKruyff RH, Umetsu DT: The many paths to asthma: Phenotype shaped by innate and adaptive immunity. Nat Immunol 2010;7:577.

Locksley RM: Asthma and allergic inflammation. Cell 2010;140:777.

Lotvall J et al: Asthma endotypes: A new approach to classification of disease entities within the asthma syndrome. J Allergy Clin Immunol 2011;127:355.

Martinez FD, Vercelli D: Asthma. Lancet 2013;382:1360.

Asthma Treatment

Bateman ED et al: Overall asthma control: The relationship between current control and future risk. J Allergy Clin Immunol 2010;125:600.

Bel EH: Mild asthma. N Engl J Med 2013;369:2362.

National Heart, Lung, and Blood Institute, National Asthma Education and Prevention Program: Expert Panel Report 3: Guidelines for the diagnosis and management of asthma. National Heart, Lung, and Blood Institute; Revised August 2007. NIH publication no. 07-4051. https://www.nhlbi.nih.gov/ health-pro/guidelines/current/asthma-guidelines.

Beta Agonists

Ducharme FM et al: Addition of long-acting beta2-agonists to inhaled steroids versus higher dose inhaled steroids in adults and children with persistent asthma. Cochrane Database Syst Rev 2010;4:CD005533.

Papi A et al: Beclomethasone-formoterol as maintenance and reliever treatment in patients with asthma: A double-blind, randomised controlled trial. Lancet Respir Med 2013;1:23.

Stempel DA et al: Serious asthma events with fluticasone plus salmeterol versus fluticasone alone. N Engl J Med 2016;374:1822.

Stempel DA et al: Safety of adding salmeterol to fluticasone propionate in children with asthma. N Engl J Med 2016;375:840.

Methylxanthines & Roflumilast

Barnes PJ: Theophylline. Am J Respir Crit Care Med 2013;188:901.

Rabe KF: Roflumilast for the treatment of chronic obstructive pulmonary disease. Expert Rev Respir Med 2010;4:543.

Cromolyn & Nedocromil

Guevara J et al: Inhaled corticosteroids versus sodium cromoglycate in children and adults with asthma. Cochrane Database Syst Rev 2006; 2:CD003558.

Corticosteroids

Barnes P: How corticosteroids control inflammation: Quintiles Prize Lecture 2005. Br J Pharmacol 2006;148:245.

Beasley R et al: Combination corticosteroid/beta-agonist inhaler as reliever therapy: A solution for intermittent and mild asthma? J Allergy Clin Immunol 2014;133:39.

Boushey HA et al: Daily versus as-needed corticosteroids for mild persistent asthma. N Engl J Med 2005;352:1519.

Suissa S et al: Low-dose inhaled corticosteroids and the prevention of death from asthma. N Engl J Med 2000;343:332.

Antimuscarinic Drugs

D’Amato M et al: Anticholinergic drugs in asthma therapy. Curr Opin Pulm Med 2016;22:527.

Lee AM, Jacoby DB, Fryer AD: Selective muscarinic receptor antagonists for airway diseases. Curr Opin Pharmacol 2001;1:223.

Peters SP et al: Tiotropium bromide step-up therapy for adults with uncontrolled asthma. N Engl J Med 2010;363:1715.

Leukotriene Pathway Inhibitors

Calhoun WJ: Anti-leukotrienes for asthma. Curr Opin Pharmacol 2001;1:230.

Laidlaw TM et al: Cysteinyl leukotriene overproduction in aspirin-exacerbated respiratory disease is driven by platelet-adherent leukocytes. Blood 2012;119:3790.

Wang L et al: Cost-effectiveness analysis of fluticasone versus montelukast in children with mild-to-moderate persistent asthma in the Pediatric Asthma Controller Trial. J Allergy Clin Immunol 2011;127:161.

Anti-IgE Therapy

Busse WW et al: Randomized trial of omalizumab (anti-IgE) for asthma in innercity children. N Engl J Med 2011;364:1005.

Walker S et al: Anti-IgE for chronic asthma in adults and children. Cochrane Database Syst Rev 2006;2:CD003559.

Targeted Monoclonal Antibody Therapy

Fainardi V, Pisi G, Chetta A: Mepolizumab in the treatment of severe eosinophilic asthma. Immunotherapy 2016;8:27.

Walsh GM: Biologics targeting IL-5, IL-4 or IL-13 for the treatment of asthma: an update. Expert Rev Clin Immunol 2017;13(2):143.

Wenzel S et al: Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: A randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet 2016;388:31.

Future Directions of Asthma Therapy

Chang TS et al: Childhood asthma clusters and response to therapy in clinical trials. J Allergy Clin Immunol 2014;133:363.

Haldar P et al: Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med 2008;178:218.

Lotvall J et al: Asthma endotypes: A new approach to classification of disease entities within the asthma syndrome. J Allergy Clin Immunol 2011; 127:355.

Moore WC et al: Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med 2010;181:315.

Woodruff PG et al: T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am J Respir Crit Care Med 2009;180:388.

Management of Acute Asthma

Lazarus SC: Clinical practice. Emergency treatment of asthma. N Engl J Med 2010;363:755.

Prospects for Prevention

Klauth M, Heine H: Allergy protection by cowshed bacteria: Recent findings and future prospects. Pediatr Allergy Immunol 2016;27:340.

Lynch SV et al: Effects of early-life exposure to allergens and bacteria on recurrent wheeze and atopy in urban children. J Allergy Clin Immunol 2014; 134:593.

Martinez FD: New insights into the natural history of asthma: Primary prevention on the horizon. J Allergy Clin Immunol 2011;128:939.

Stein MM et al: Innate immunity and asthma risk in Amish and Hutterite farm children. N Engl J Med 2016;375:411.

Treatment of COPD

Global Initiative for Chronic Obstructive Lung Disease: Global Strategy for Diagnosis, Management, and Prevention of COPD. http://www

.goldcopd.org.

Huisman EL et al: Comparative efficacy of combination bronchodilator therapies in COPD: A network meta-analysis. Int J Chron Obstruct Pulmon Dis 2015;10:1863.

Kew KM, Dias S, Cates CJ: Long-acting inhaled therapy (beta-agonists, anticholinergics and steroids) for COPD: A network meta-analysis. Cochrane Database Syst Rev 2014;1:CD010844.

Niewoehner DE: Clinical practice. Outpatient management of severe COPD. N Engl J Med 2010;362:1407.

Vogelmeier C et al: Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med 2011;364:1093.

C A S E S T U D Y A N S W E R

This patient demonstrates the destabilizing effects of a respiratory infection on asthma, and her mother’s comments demonstrate the common (and dangerous) phobia about “overuse” of bronchodilator or steroid inhalers. The patient has signs of imminent respiratory failure, including her refusal to lie down, her fear, and her tachycardia, which cannot be attributed to her minimal treatment with albuterol. Critically important immediate steps are to administer highflow oxygen and to start albuterol by nebulization. Adding ipratropium (Atrovent) to the nebulized solution is recommended. A corticosteroid (0.5–1.0 mg/kg of methylprednisolone) should be administered intravenously. It is also advisable to alert the intensive care unit, because a patient with severe bronchospasm who tires can slip into respiratory failure quickly, and intubation can be difficult.

Fortunately, most patients treated in hospital emergency departments do well. Asthma mortality is rare (fewer than 4000 deaths per year among a population of more than 20 million asthmatics in the USA), and when it occurs, it is often out of hospital. Presuming this patient recovers, she needs adjustments to her therapy before discharge. The strongest predictor of severe attacks of asthma is their occurrence in the past. Thus, this patient’s therapy needs to be stepped up to a higher level, like a high-dose inhaled corticosteroid in combination with a long-acting βagonist. Both the

patient and her parents need instruction on the importance of regular adherence to therapy, with reassurance that it can be “stepped down” to a lower dose of inhaled corticosteroid (although still in combination with a long-acting β agonist) once her condition stabilizes. They also need instruction on an action plan for managing severe symptoms. This can be as simple as advising that if the patient has a severe, frightening attack, she can take up to four puffs of albuterol every 15 minutes, but if the first treatment does not bring significant relief, she should take the next four puffs while on her way to an emergency department or urgent care clinic. She should also be given a prescription for prednisone, with instructions to take 40–60 mg orally for severe attacks, but not to wait for it to take effect if she remains severely short of breath even after albuterol inhalations. Asthma is a chronic disease, and good care requires close follow-up and creation of a provider-patient partnership for optimal management. If she has had several previous exacerbations, she should be considered a candidate for monoclonal anti-IgE antibody therapy with omalizumab, which effectively reduces the rate of asthma exacerbations—even those associated with viral respiratory infection—in patients with allergic asthma. Alternatively, if the patient is found to have blood eosinophilia, treatment with an anti-IL-5 monoclonal antibody (eg, mepolizumab) should be considered as well.

Drugs acting in the central nervous system (CNS) were among the first to be discovered by primitive humans and are still the most widely used group of pharmacologic agents. These include medications used to treat a wide range of neurologic and psychiatric conditions as well as drugs that relieve pain, suppress nausea, and reduce fever, among other symptoms. In addition, many CNS-acting drugs are used without prescription to increase the sense of well-being.

Due to their complexity, the mechanisms by which various drugs act in the CNS have not always been clearly understood. In recent decades, however, dramatic advances have been made in the methodology of CNS pharmacology. It is now possible to study the action of a drug on individual neurons and even single receptors within synapses. The information obtained from such studies is the basis for several major developments in studies of the CNS. First, it is clear that nearly all drugs with CNS effects act on specific receptors that modulate synaptic transmission. While a few agents such as general anesthetics and alcohol may have nonspecific actions on membranes (although these exceptions are not

The author thanks Dr. Roger A. Nicoll for his contributions to previous editions.

fully accepted), even these non–receptor-mediated actions result in demonstrable alterations in synaptic transmission.

Second, drugs are among the most valuable tools for studying CNS function, from understanding the mechanism of convulsions to the laying down of long-term memory. Both agonists that mimic natural transmitters (and in many cases are more selective than the endogenous substances) and antagonists are extremely useful in such studies. Third, unraveling the actions of drugs with known clinical efficacy has led to some of the most fruitful hypotheses regarding the mechanisms of disease. For example, information about the action of antipsychotic drugs on dopamine receptors has provided the basis for important hypotheses regarding the pathophysiology of schizophrenia. Studies of the effects of a variety of agonists and antagonists on γ-aminobutyric acid (GABA) receptors have resulted in new concepts pertaining to the pathophysiology of several diseases, including anxiety and epilepsy.

A full appreciation of the effects of a drug on the CNS requires an understanding of the multiple levels of brain organization, from genes to circuits to behavior. This chapter provides an introduction to the functional organization of the CNS and its synaptic transmitters as a basis for understanding the actions of the drugs described in the following chapters.

ORGANIZATION OF THE CNS

The CNS is composed of the brain and spinal cord and is responsible for integrating sensory information and generating motor output and other behaviors needed to successfully interact with the environment and enhance species survival. The human brain contains about 100 billion interconnected neurons surrounded by various supporting glial cells. Throughout the CNS, neurons are either clustered into groups called nuclei or are present in layered structures such as the cerebellum or hippocampus. Connections among neurons both within and between these clusters form the circuitry that regulates information flow through the CNS.

Neurons

Neurons are electrically excitable cells that process and transmit information via an electrochemical process. There are many types of neurons in the CNS, and they are classified in multiple ways: by function, by location, and by the neurotransmitter they release. The typical neuron, however, possesses a cell body (or soma) and specialized processes called dendrites and axons (Figure 21–1). Dendrites, which form highly branched complex dendritic “trees,” receive and integrate the input from other neurons and conduct this information to the cell body. The axon carries the output signal of a neuron from the cell body, sometimes over long distances. Neurons may have hundreds of dendrites but generally have only one axon, although axons may branch distally to contact multiple targets. The axon terminal makes contact with other neurons at specialized junctions called synapses where neurotransmitter chemicals are released that interact with receptors on other neurons.

Neuroglia

In addition to neurons, there are a large number of nonneuronal support cells, called glia, that perform a variety of essential

functions in the CNS. Astrocytes are the most abundant cell in the brain and play homeostatic support roles, including providing metabolic nutrients to neurons and maintaining extracellular ion concentrations. In addition, astrocyte processes are closely associated with neuronal synapses where they are involved in the removal and recycling of neurotransmitters after release and play increasingly appreciated roles in regulating neurotransmission (see below).

Oligodendrocytes are cells that wrap around the axons of projection neurons in the CNS forming the myelin sheath (Figure 21–1). Similar to the Schwann cells in peripheral neurons, the myelin sheath created by the oligodendrocytes insulates the axons and increases the speed of signal propagation. Damage to oligodendrocytes occurs in multiple sclerosis, and thus, they are a target of drug discovery efforts.

Microglia are specialized macrophages derived from the bone marrow that settle in the CNS and are the major immune defense system in the brain. The cells are actively involved in neuroinflammatory processes in many pathological states including neurodegenerative diseases.

Blood-Brain Barrier

The blood-brain barrier (BBB) is a protective functional separation of the circulating blood from the extracellular fluid of the CNS that limits the penetration of substances, including drugs. This separation is accomplished by the presence of tight junctions between the capillary endothelial cells as well as a surrounding layer of astrocyte end-feet. As such, to enter the CNS, drugs must either be highly hydrophobic or engage specific transport mechanisms. For example, the second-generation antihistamines cause less drowsiness because they were developed to be significantly more polar than older antihistamines, limiting their crossing of the BBB (see Chapter 16). Many nutrients, such as glucose and the essential amino acids, have specific transporters that allow them to cross the BBB. -DOPA, a precursor of the neurotransmitter dopamine, can enter the brain

using an amino acid transporter, whereas dopamine cannot cross the BBB. Thus, the orally administered drug -DOPA, but not dopamine, can be used to boost CNS dopamine levels in the treatment of Parkinson’s disease. Some parts of the brain, the so-called circumventricular organs, lack a normal BBB.These include regions that sample the blood, such as the area postrema vomiting center, and regions that secrete neurohormones into the circulation.

ION CHANNELS & NEUROTRANSMITTER RECEPTORS

The membranes of neurons contain two types of channels defined on the basis of the mechanisms controlling their gating (opening and closing): voltage-gated and ligand-gated channels (Figure 21–2A and B). Voltage-gated channels respond

to changes in the membrane potential of the cell. The voltage-gated sodium channel described in Chapter 14 for the heart is an example of this type of channel. In nerve cells, these channels are highly concentrated on the initial segment of the axon (Figure 21–1), which initiates the all-or-nothing fast action potential, and along the length of the axon where they propagate the action potential to the nerve terminal. There are also many types of voltage-sensitive calcium and potassium channels on the cell body, dendrites, and initial segment, which act on a much slower time scale and modulate the rate at which the neuron discharges. For example, some types of potassium channels opened by depolarization of the cell result in slowing of further depolarization and act as a brake to limit further action potential discharge. Plant and animal toxins that target various voltage-gated ion channels have been invaluable for studying the functions of these channels (see Box: Natural Toxins: Tools for Characterizing Ion Channels; Table 21–1).

Natural Toxins: Tools For Characterizing

Ion Channels

Evolution is tireless in the development of natural toxins. A vast number of variations are possible with even a small number of amino acids in peptides, and peptides make up only one of a broad array of toxic compounds. For example, the predatory marine snail genus Conus includes over 3000 different species. Each species kills or paralyzes its prey with a venom that contains 50–200 different peptides or proteins. Furthermore, there is little duplication of peptides among Conus species. Other animals with useful toxins include snakes, frogs, spiders, bees, wasps, and scorpions. Plant species with toxic (or therapeutic) substances are referred to in several other chapters of this book.

Since many toxins act on ion channels, they provide a wealth of chemical tools for studying the function of these channels. In fact, much of our current understanding of the properties of ion channels comes from studies utilizing only a small percentage of the highly potent and selective toxins that are now available. The toxins typically target voltagesensitive ion channels, but a number of very useful toxins block ligand-gated ion channels receptors. Table 21–1 lists some of the toxins most commonly used in research, their mode of action, and their source.

Neurotransmitters exert their effects on neurons by binding to two distinct classes of receptor. The first class is referred to as ligand-gated channels, or ionotropic receptors. These receptors consist of multiple subunits, and binding of the neurotransmitter ligand directly opens the channel, which is an integral part of the receptor complex (see Figure 22–6). These channels are insensitive or only weakly sensitive to membrane potential. Activation of these channels typically results in a brief (a few milliseconds to tens of milliseconds) opening of the channel. Ligand-gated channels are responsible for fast synaptic transmission typical of hierarchical pathways in the CNS (see following text).

The second class of neurotransmitter receptor is referred to as metabotropic receptors (Figure 21–2C). These are seventransmembrane G protein-coupled receptors of the type described in Chapter 2. The binding of neurotransmitter to this type of receptor does not result in the direct gating of a channel. Rather, binding to the receptor engages a G protein, which results in the production of second messengers that mediate intracellular signaling cascades such as those described in Chapter 2.

In neurons, activation of metabotropic neurotransmitter receptors often leads to the modulation of voltage-gated channels. These interactions can occur entirely within the plane of the membrane and are referred to as membrane-delimited pathways (Figure 21–2D). In this case, the G protein (often the βγ subunit) interacts directly with a voltage-gated ion channel. In general, two types of voltage-gated ion channels are the targets of this type of signaling: calcium channels and potassium channels. When G proteins interact with calcium channels, they inhibit channel

TABLE 21 1 Some toxins used to characterize ion channels.

function. This mechanism accounts for the inhibition of neurotransmitter release that occurs when presynaptic metabotropic receptors are activated. In contrast, when these receptors are postsynaptic, they activate (cause the opening of) potassium channels, resulting in a slow postsynaptic inhibition. Metabotropic receptors can also modulate voltage-gated channels less directly by the generation of diffusible second messengers (Figure 21–2E). A classic example of this type of action is provided by the β adrenoceptor, which generates cAMP via the activation of adenylyl cyclase (see Chapter 2). Whereas membrane-delimited actions occur within microdomains in the membrane, second messengermediated effects can occur over considerable distances. Finally, an important consequence of the involvement of G proteins in receptor signaling is that, in contrast to the brief effect of ionotropic receptors, the effects of metabotropic receptor activation can last tens of seconds to minutes. Metabotropic receptors predominate in the diffuse neuronal systems in the CNS (see below).

THE SYNAPSE & SYNAPTIC POTENTIALS

The communication between neurons in the CNS occurs through chemical synapses in the majority of cases. (A few instances of electrical coupling between neurons have been documented,

and such coupling may play a role in synchronizing neuronal discharge. However, it is unlikely that these electrical synapses are an important site of drug action.) The events involved in synaptic transmission can be summarized as follows.

An action potential propagating down the axon of the presynaptic neuron enters the synaptic terminal and activates voltagesensitive calcium channels in the membrane of the terminal (see Figure 6–3). The calcium channels responsible for the release of neurotransmitter are generally resistant to the calcium channelblocking agents discussed in Chapter 12 (eg, verapamil) but are sensitive to blockade by certain marine toxins and metal ions (see Tables 21–1 and 12–4). As calcium flows into the terminal, the increase in intraterminal calcium concentration promotes the fusion of synaptic vesicles with the presynaptic membrane. The neurotransmitter contained in the vesicles is released into the synaptic cleft and diffuses to the receptors on the postsynaptic membrane. The neurotransmitter binds to its receptor and opens channels (either directly or indirectly as described above) causing a brief change in membrane conductance (permeability to ions) of the postsynaptic cell. The time delay from the arrival of the presynaptic action potential to the onset of the postsynaptic response is approximately 0.5 ms. Most of this delay is consumed by the release process, particularly the time required for calcium channels to open.

The first systematic analysis of synaptic potentials in the CNS was in the early 1950s by Eccles and associates, who recorded intracellularly from spinal motor neurons. When a microelectrode enters a cell, there is a sudden change in the potential recorded by the electrode, which is typically about −60 mV (Figure 21–3A). This is the resting membrane potential of the neuron. Two types of pathways—excitatory and inhibitory—impinge on the motor neuron.

When an excitatory pathway is stimulated, a small depolarization or excitatory postsynaptic potential (EPSP) is recorded. This potential is due to the excitatory transmitter acting on an ionotropic receptor, causing an increase in cation permeability. As additional excitatory synapses are activated, there is a graded summation of the EPSPs to increase the size of the depolarization (Figure 21–3A, spatial summation, middle). When a sufficient number of excitatory synapses are activated, the excitatory postsynaptic potential depolarizes the postsynaptic cell to threshold, and an all-or-none action potential is generated. Alternatively, if there is a repetitive firing of an excitatory input, the temporal summation of the EPSPs may also reach the action potential threshold (Figure 21–3A, right).

When an inhibitory pathway is stimulated, the postsynaptic membrane is hyperpolarized owing to the selective opening of chloride channels, producing an inhibitory postsynaptic potential (IPSP) (Figure 21–3B, middle). However, because the equilibrium potential for chloride (see Chapter 14) is only slightly more negative than the resting potential ( −65 mV), the hyperpolarization is small and contributes only modestly to the inhibitory action. The opening of the chloride channel during the inhibitory postsynaptic potential makes the neuron “leaky” so that changes in membrane potential are more difficult to achieve. This shunting effect decreases the change in membrane potential during the excitatory postsynaptic potential. As a result, an EPSP

FIGURE 21 3 Postsynaptic potentials and action potential generation. A shows the voltage recorded upon entry of a microelectrode into a postsynaptic cell and subsequent recording of a resting membrane potential of −60 mV. Stimulation of an excitatory pathway (E1, left) generates transient depolarization called an excitatory postsynaptic potential (EPSP). Simultaneous activation of multiple excitatory synapses (E1 + E2, middle) increases the size of the depolarization, so that the threshold for action potential generation is reached. Alternatively, a train of stimuli from a single input can temporally summate to reach the threshold (E1 + E2, right). B demonstrates the interaction of excitatory and inhibitory synapses. On the left, a suprathreshold excitatory stimulus (E3) evokes an action potential. In the center, an inhibitory pathway (I) generates a small hyperpolarizing current called an inhibitory postsynaptic potential (IPSP). On the right, if the previously suprathreshold excitatory input (E3) is given shortly after the inhibitory input (I), the IPSP prevents the excitatory potential from reaching threshold.

that evoked an action potential under resting conditions fails to evoke an action potential during the IPSP (Figure 21–3B, right). A second type of inhibition is presynaptic inhibition. It was first described for sensory fibers entering the spinal cord, where excitatory synaptic terminals receive synapses called axoaxonic synapses (described later). When activated, axoaxonic synapses reduce the amount of transmitter released from the terminals of sensory fibers. It is interesting that presynaptic inhibitory receptors are present on almost all presynaptic terminals in the brain even though axoaxonic synapses appear to be restricted to the spinal cord. In the brain, transmitter can spill out of the synapse and activate presynaptic receptors, either on the same synapse (autoreceptors) or on neighboring synapses.

SITES OF DRUG ACTION

Virtually all the drugs that act in the CNS produce their effects by modifying some step in chemical synaptic transmission. Figure 21–4 illustrates some of the steps that can be altered. These transmitter-dependent actions can be divided into presynaptic and postsynaptic categories.

Drugs acting on the synthesis, storage, metabolism, and release of neurotransmitters fall into the presynaptic category. Synaptic transmission can be depressed by blockade of transmitter synthesis or storage. For example, reserpine depletes monoamine synapses of transmitters by interfering with intracellular storage. Blockade of transmitter catabolism inside the nerve terminal can increase transmitter concentrations and has been reported to increase the amount of transmitter released per impulse. Drugs can also alter the release of transmitters. The stimulant amphetamine induces the release of catecholamines from adrenergic synapses (see Chapters 6, 9, and 32). Capsaicin causes the release of the peptide substance P from sensory neurons, and tetanus toxin blocks the release of transmitters. After a CNS transmitter has been released into the synaptic cleft, its action is terminated either by uptake or by degradation. For most neurotransmitters, there are uptake mechanisms into the synaptic terminal and also into surrounding neuroglia. Cocaine, for example, blocks the uptake of catecholamines at adrenergic synapses and thus potentiates the action of these amines. Acetylcholine, however, is inactivated by enzymatic degradation, not reuptake. Anticholinesterases block the degradation of acetylcholine and thereby prolong its action (see Chapter 7). No uptake mechanism has been found for any of the numerous CNS peptides, and it has yet to be demonstrated whether specific enzymatic degradation terminates the action of peptide transmitters.

In the postsynaptic region, the transmitter receptor provides the primary site of drug action. Drugs can act either as neurotransmitter agonists, such as the opioids, which mimic the action of enkephalin, or they can block receptor function. Receptor antagonism is a common mechanism of action for CNS drugs. An example is strychnine’s blockade of the receptor for the inhibitory transmitter glycine. This block, which underlies strychnine’s convulsant action, illustrates how the blockade of inhibitory processes results in excitation. Drugs can also act directly on the ion channel of ionotropic receptors. For example, the anesthetic ketamine blocks the NMDA subtype of glutamate ionotropic receptors by binding in the ion channel pore. In the case of metabotropic receptors, drugs can act at any of the steps downstream of the receptor. Perhaps the best example is provided by the methylxanthines, which can modify neurotransmitter responses mediated through the second-messenger cAMP. At high concentrations, the methylxanthines elevate the level of cAMP by blocking its metabolism and thereby prolong its action.

The traditional view of the synapse is that it functions like a valve, transmitting information in one direction. However, it is now clear that the synapse can generate signals that feed back onto the presynaptic terminal to modify transmitter release. Endocannabinoids are the best documented example of such retrograde signaling (see below). Postsynaptic activity leads to the synthesis